tbuckley/cabot-search huggingface dataset:
Abstract 3652: Circular RNAs repress interferon responses in the sarcoma cells and promote sarcoma growth by forging a pro-tumorigenic immune microenvironment
Authors: Jlenia Guarnerio
Journal: Cancer Research (2023)

Abstract Circular RNAs (CircRNA) arise from events of non-conventional splicing in which the 3'-tail of an exon back-splices and joins the 5'-head of the upstream exon. Because of their structural conformation, these RNAs are incredibly stable in the cellular space, where they can regulate tumor-associated and anti-immunogenic pathways. Although circRNAs have been profiled in many tumors, their functional contribution to cancer progression is still poorly understood. In the current study, we profiled the most abundant circRNAs expressed in Soft-tissue sarcomas (STS) and characterized them functionally and mechanistically. Surgery and chemotherapy are the standard treatments for STS, but the 5-year survival rate is still below 20% for the advanced cases. Response to immunotherapies, such as immune checkpoint inhibitors, is also marginal for STS, likely because sarcoma cells are not sufficiently immunogenic to recruit a high volume of cytotoxic T cells. To implement discoveries on STS, we recently generated novel immunocompetent STS mouse models and characterized the sarcoma-elicited mechanisms to block immune-recruitment. Interestingly, we observed that two circRNAs, circCsnk1g3, and circAnkib1, promote sarcoma growth by shaping a pro-tumorigenic microenvironment, possibly due to their capabilities to regulate tumor-promoting elements extrinsic to the sarcoma cells. More specifically, we observed that circCsnk1g3 and circAnkib1 control the expression of interferon-related genes and pro-inflammatory factors in the sarcoma cells, thus directing immune cell recruitment into the tumor mass and hence their activation. Mechanistically, we observed that circRNAs might repress pro-inflammatory elements by buffering activation of the pathways mediated by RIG-I, the cytosolic viral RNA sensor. The current findings suggest that targeting specific circRNAs could augment the efficacy of sarcoma immune response to mainstay therapies. Citation Format: Jlenia Guarnerio. Circular RNAs repress interferon responses in the sarcoma cells and promote sarcoma growth by forging a pro-tumorigenic immune microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3652.
Abstract 6753: Non-HIV cryptococcal patients with hematological malignancies: A retrospective analysis of a ten-year study from a Peruvian oncologic center
Authors: Kelly Meza, Luis E. Cuellar
Journal: Cancer Research (2023)

Abstract Background Globally, cryptococcal infection has become a public health challenge. However, relatively little is known about cryptococcal infection in people with hematological disorders. Methods We developed a retrospective cohort study that includes hematological patients who had cryptococcosis infection seen in the Instituto Nacional de Enfermedades Neoplasicas between 2007 and 2017. Results During the 11-year study period, a total of 21 cases of cryptococcosis (incidence rate of 13,4 per 1000 hematological malignancies). The time of diagnosis of cryptococcosis since hematologic malignancy diagnosis was 42 (18-161) days. Non-Hodgkin lymphoma (NHL) was the most frequent malignancy (47.6%), followed by leukemias (23.8%), multiple myeloma in (19.1%), and HL (9.5%). Three cases of adult T-cell leukemia/lymphoma associated with HTLV-1 infection were identified in the NHL. Cryptococcemia was the most frequent diagnosis (85.7%) followed by pulmonary (52.4%) and CNS (38.1%) involvement. Regarding clinical presentation, f ever was the most common symptom in meningeal cryptococcosis (76.2%) and dyspnea in pulmonary cryptococcosis (61.9%). The use of immunosuppressant chemotherapy within a month before the diagnosis of cryptococcosis was the most common risk factor. The main characteristics between patients with cryptococcosis and type of neoplasms (NHL vs other hematological neoplasms) such as age at admission, site of presentation of cryptococcosis, and lymphocyte count at admission were different significantly between these groups. In the NHL group, there was less involvement of the lungs. Overall survival (OS) in 15 and 120 days were 70% (95%CI: 0.43-0.86) and 51% (95%CI: 0.26-0.72), respectively. OS for patients with NHL was 57% at 15 days (95% CI: 0.17-0.83) and 42% at 120 days (95%CI:0.09-0.73). OS for other hematological malignancies was 90% at 15 days (95%CI:0.47-0.98) and 60% at 120 days (95%CI: 0.25-0.82). Conclusions CNS cryptococcal infection was more frequent in patients with NHL. Citation Format: Kelly Meza, Luis E. Cuellar. Non-HIV cryptococcal patients with hematological malignancies: A retrospective analysis of a ten-year study from a Peruvian oncologic center. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6753.
Abstract 1833: Novel IL-12 Partial Agonist For Cancer Immunotherapy Avoids NK-cell Mediated Toxicity
Authors: Ievgen Koliesnik, Jan Emmerich, Kim Q. Tran, Michele Bauer, Michael Totagrande, Bhargavi Jayaraman, Cindy Buffone, Priyanka Balasubrahmanyam, Deepti Rokkam, Rene de Waal Malefyt, Luis Zuniga, Heiko Greb, Navneet Ratti, Sandro Vivona, Martin Oft, Patrick J. Lupardus, Robert A. Kastelein
Journal: Cancer Research (2023)

Abstract Here we report on a novel human IL-12 partial agonist (hIL-12v) that has diminished binding to IL-12Rb1. IL-12v is designed to more selectively engage antigen activated T-cells, which strongly upregulate IL-12Rb1 upon activation, and to reduce stimulation of NK cells or resting T cells, which express modest levels of IL-12Rb1. To explore anti-tumor efficacy and toxicity in mouse syngeneic tumor models, we generated a half-life extended mouse surrogate of the IL-12 partial agonist (mIL-12v Fc) and compared it to a similarly engineered half-life extended version of wild type mouse IL-12 (mIL-12wt Fc). At efficacious doses, systemic administration of mIL-12wt Fc induced significant weight loss and lethality characterized by early proinflammatory cytokine release and systemic NK cell activation. Conversely, mIL-12v Fc was well tolerated and avoided the robust and rapid NK cell activation and peripheral NK count decreases seen with mIL-12v Fc, suggestive of extravasation to tissues. Both mIL-12v Fc and mIL-12 WT Fc showed similar robust single-agent anti-tumor efficacy in syngeneic tumor models. Depletion of NK cells did not diminish anti-tumor efficacy. Efficacy for both molecules was characterized by CD8 T cell activation, myeloid cell reprograming and antigen presentation. Moreover, combination of mIL-12v Fc with systemic immunotherapies further enhanced anti-tumor activity without compromising tolerability. Overall, mIL-12v Fc retained anti-tumor efficacy without induction of severe toxicities compared to mIL-12wt Fc. These data suggest IL-12 partial agonists may represent a novel immunotherapy approach to maintain efficacy while avoiding classical toxicity associated with IL-12 therapy.1 Atkins, et al.; (1997) Clinical Cancer Research 3(3):409-172 Carson, et al. (1999) J Immunology 162 (8): 4943-4951. Citation Format: Ievgen Koliesnik, Jan Emmerich, Kim Q. Tran, Michele Bauer, Michael Totagrande, Bhargavi Jayaraman, Cindy Buffone, Priyanka Balasubrahmanyam, Deepti Rokkam, Rene de Waal Malefyt, Luis Zuniga, Heiko Greb, Navneet Ratti, Sandro Vivona, Martin Oft, Patrick J. Lupardus, Robert A. Kastelein. Novel IL-12 Partial Agonist For Cancer Immunotherapy Avoids NK-cell Mediated Toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1833.
Abstract 5135: Standardized off-the-shelf engineered NK cell therapy with improved ADCC properties to treat malignancies
Authors: Yanan Lin, Shengbang Zhang, Jie Ran, Can Song, Shengcang Zhu, Hui Shi, Ping Guo, Shengjiang Tan, Yuchun Gu, Lida Wu
Journal: Cancer Research (2023)

Abstract In the treatment of solid tumors, chimeric antigen receptor(CAR)-engineered NK (CAR-NK) cells have distinct advantages over CAR-T cells, such as a lack graft-versus-host disease in allogenic setting to make “off the shelf” medicine; much safer because they are less likely to cause cytokine storms; and NK cells have their own activated receptors that recognize tumor surface antigens and thus have a natural ability to kill a wide range of tumors. In addition, NK cells are the main performers of antibody-dependent cell-mediated cytotoxicity (ADCC), which binds to the Fc-terminus of antibodies through their surface Fc receptor CD16A, thereby killing antibody-targeted tumor cells. Enhancing the ADCC action of NK cells themselves enhances the therapeutic efficacy of monoclonal antibodies targeting tumor surface antigens and is therefore of great importance in the treatment of tumors, especially solid tumors. We screened two optimal structures among nine different Fc chimeric receptors, and NK cells overexpressing these two receptors killed K562 and Daudi six times more intensely than normal NK cells when combined with rituximab, while the killing ability was comparable to that of normal NK without rituximab, indicating that NK cells expressing chimeric Fc receptors have stronger ADCC effects. Moreover, these NK cells can kill target cells in multiple rounds. In vivo experiments in mice demonstrated that NK cells expressing chimeric Fc receptors in combination with EGFR monoclonal antibodies had a stronger inhibitory effect on tumor growth than monoclonal antibodies or NK cells alone. Here we provide a novel broad “off the shelf” NK cells that can significantly enhance the killing ability of hematological and solid tumors in combination with different monoclonal antibodies. Citation Format: Yanan Lin, Shengbang Zhang, Jie Ran, Can Song, Shengcang Zhu, Hui Shi, Ping Guo, Shengjiang Tan, Yuchun Gu, Lida Wu. Standardized off-the-shelf engineered NK cell therapy with improved ADCC properties to treat malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5135.
Abstract 4588: Vascular regulation of T-cell exclusion in melanoma
Authors: Ha-Ram Park, Anahita Shiva, Portia Cummings, Richard Carvajal, Gavin Thurston, Joon-Yong An, Amanda W. Lund, Hee Won Yang, Minah Kim
Journal: Cancer Research (2023)

Abstract T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T-cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T-cell infiltration within tumor. We analyzed the spatial regulation of ANGPT2 in whole tumor cross-sections and its impact on CD8+ T-cell position, vascular integrity, and response to immunotherapy using syngeneic murine melanomas. We found that T-cell exclusion was associated with peritumoral expression of ANGPT2 and elevated vascular leakage in human and murine melanomas. Both pharmacological and genetic blockade of ANGPT2 promoted CD8+ T-cell infiltration to the tumor core, exerting antitumor effects. Importantly, the reversal of T-cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 therapy in immunogenic, therapy responsive mouse melanomas, but also rendered non-responsive tumors susceptible. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ T-cell infiltration, coincided with TIE2 signaling activation and increased vascular integrity in the tumor periphery, indicating that maintenance of vascular integrity within tumors is necessary for robust response to immunotherapy. These data highlight ANGPT2/TIE2 signaling as a key mediator of T-cell exclusion and a promising target to potentiate checkpoint inhibitor efficacy in melanoma. Citation Format: Ha-Ram Park, Anahita Shiva, Portia Cummings, Richard Carvajal, Gavin Thurston, Joon-Yong An, Amanda W. Lund, Hee Won Yang, Minah Kim. Vascular regulation of T-cell exclusion in melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4588.
Abstract 239: Whole-genome sequencing based homologous recombination deficiency testing for precision oncology of breast cancers
Authors: Ryul Kim, Seongyeol Park, Joonoh Lim, Boram Yi, Jaemo Koo, Sangmoon Lee, Jeong Seok Lee, Yeon Hee Park, Young Seok Ju
Journal: Cancer Research (2023)

Abstract Breast cancers (BCs) with defects in homologous recombination repair (HRR) pathway depend on the Poly (ADP-ribose) polymerase enzymes (PARP) for their survival and thus are sensitive to PARP inhibitors (PARPi). To screen out BCs with homologous recombination deficiency (HRD), germline mutations in BRCA genes have been tested, which constitute approximately 5% of unselected BC patients. However, a substantial proportion of BCs show HRD phenotypes despite the absence of BRCA inactivating mutations in germline. Herein, we apply whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS) in 332 samples from 325 BC patients for characterizing their HRD phenotypes for PARPi treatments. Of 325 BC patients, 75 cases (23.1%) showed remarkable HRD phenotypes, based on mutational signatures of HRR abrogation. Intriguingly, 51 cases do not harbor any germline mutations in HR-related genes including BRCA1 and BRCA2. The whole-genome portrait of these samples was similar to that of HRD-positive BCs with germline mutation in HRR pathway, but showed markedly distinctive features from HRD-negative BCs. With a notable exception of BRCA1, the second most common somatic mutation in HRD-positive BCs without germline mutation, the mutational landscape of the whole study samples was primarily determined by hormone receptor and HER2 positivity, not by HRD status. Likewise, WTS-based clusters determined in an unsupervised manner were highly dependent on the histological subtype of BC, not on HRD status or germline mutations in the HRR pathway. Notably, differentially expressed gene and gene set enrichment analysis revealed that HRD-positive BCs had an increased inflammatory activity compared to BCs with proficient HR. Overall, our analysis demonstrate that WGS enables better classification of the HR status in BC than conventional BRCA germline testing, suggesting WGS as a rapid and sensitive tool for screening breast cancers for PARPi treatment. Citation Format: Ryul Kim, Seongyeol Park, Joonoh Lim, Boram Yi, Jaemo Koo, Sangmoon Lee, Jeong Seok Lee, Yeon Hee Park, Young Seok Ju. Whole-genome sequencing based homologous recombination deficiency testing for precision oncology of breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 239.
Abstract 2204: Predicting survival outcomes in patients with acute myeloid leukemia: medium-sized versus large next-generation sequencing panels
Authors: Yonghong Li, Jose Solis-Ruiz, Frederick K. Racke, Richard D. Press
Journal: Cancer Research (2023)

Abstract Background: Next-generation sequencing (NGS) multigene panels allow the identification of genetic variants in patients with acute myeloid leukemia (AML). This study assessed the effect of the NGS panel size on positivity rate and clinic utility in helping predict survival outcomes. Design: This is a retrospective study of AML patients (n=76) who underwent both diagnostic and post-treatment testing with a large 220-gene NGS assay. Mutation profiles and measurable residual disease (MRD) status were assessed with the large panel or a subset of the genes on the panel (i.e., a medium-sized panel with 42 genes); MRD assessment excluded DTA mutations (i.e., mutations in preleukemic genes DNMT3A, TET2 and ASXL1). Kaplan-Meier method was used to compare overall survival between MRD positive and negative patients. Results: The 76 patients evaluated were diagnosed with de novo AML (n=69) or secondary AML (n=7). The median age at diagnosis was 57 (interquartile range [IQR], 49-66) years; 37 (49%) were women; and the median follow-up was 273 (IQR, 174-473) days. At diagnosis, the medium-sized panel detected 276 somatic variants in 35 genes (average 3.6 variants per patient) whereas the large panel detected 351 somatic variants in 74 genes (average 4.6 variants per patient). These variants were frequently detected in methylation and epigenetic genes (25%), signaling genes (20%) and transcription factors (12%). After treatment, MRD-negativity was indicated in 27 patients by the medium-sized panel versus 23 patients by the large panel; MRD-positivity was indicated in 49 patients by the medium-sized panel versus 53 patients by the large panel. Shorter overall survival was associated with MRD-positivity as determined by both panels: medium-sized panel (hazard ratio [HR], 3.00; 95% CI, 1.01-8.93; P&amp;lt;.05), large panel (HR, 3.41; 95% CI, 1.00-11.57; P&amp;lt;.05). Conclusion: A medium-sized NGS panel detected fewer somatic mutations than large NGS panel but both panels, when used as MRD markers, are similarly predictive of overall survival in AML patients. Citation Format: Yonghong Li, Jose Solis-Ruiz, Frederick K. Racke, Richard D. Press. Predicting survival outcomes in patients with acute myeloid leukemia: medium-sized versus large next-generation sequencing panels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2204.
Abstract 4276: Recovering false negatives in CRISPR fitness screens with JLOE
Authors: Merve Dede, Traver Hart
Journal: Cancer Research (2023)

Abstract It is widely accepted that pooled library CRISPR-Cas9 knockout screens offer greater sensitivity and specificity than prior technologies in detecting essential genes whose disruption leads to fitness defects, a critical step in identifying candidate cancer targets. However, the assumption that CRISPR screens are saturating has been largely untested and it is still poorly understood whether possible systematic biases in CRISPR screens affect our understanding of human cell-intrinsic gene essentiality. In the absence of a ground truth, the actual true positive, false positive and false negative rates of a typical genome-wide CRISPR-Cas9 knockout screen are still unknown. Through integrated analysis of screen data in hundreds of cancer cell lines generated by the Cancer Dependency Map, we examine some of the biases characteristic of genome-wide CRISPR-Cas9 knockout screening. With our computational modeling approaches, we estimate the true positive rate, false positive rate and show that a typical CRISPR screen has a ~20% false negative rate, in addition to library-specific false negatives. Furthermore, replicability of essential gene hits falls sharply as gene expression decreases, while cancer subtype-specific genes within a tissue show distinct profiles compared to false negatives. With our cumulative analyses across tissues, we identified an improved new set of core essential genes, which, like the previous set, can be used as a metric for the quality control of genome-wide CRISPR-Cas9 knockout screens. Our results also suggest only a small number of lineage-specific essential genes, with the overwhelming majority of genes showing overlap between related tissues and are enriched for transcription factors that define pathways of tissue differentiation. To recover false negatives in these genome- wide CRISPR knockout screens, we introduce a method called Joint Log Odds of Essentiality (JLOE), which extends fundamental concepts from our Bayesian framework of BAGEL algorithm to improve analysis across multiple cell line screens. JLOE uses information derived from previous screens to update the probability of essentiality of each screen based on prior observations. We show that JLOE selectively rescues the false negatives without an increased false discovery rate and improves screen concordance with the Sanger dataset, reducing the number of background-specific essential genes. Overall, our methods offer a significantly improved analysis of genome-wide CRISPR-Cas9 knockout screens, detecting and correcting for the previously unidentified false negatives and enhancing our identification of cancer-specific vulnerabilities as therapeutic targets. Citation Format: Merve Dede, Traver Hart. Recovering false negatives in CRISPR fitness screens with JLOE. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4276.
Abstract 4766: Hypoxia increases the methylated histones to prevent histone clipping during Raf-induced senescence
Authors: Hyunsung Park, Soojeong Chang
Journal: Cancer Research (2023)

Abstract Hypoxia increases methylated histones by inhibiting O2- and α-ketoglutarate-dependent histone lysine demethylases (KDMs). This study is the first to demonstrate how the hypoxic increment of methylated histones cross-talks with other epigenetic changes, such as histone clipping and heterochromatin redistribution, named senescence-associated heterochromatin foci (SAHF), which are found during oncogene-induced senescence (OIS). Raf-activation in primary human fibroblasts IMR90 increases mature cathepsin L (CTSL)-mediated clipping of histone H3, H2B and H4. Hypoxia protects histones from CTSL by increasing histone methylation without reducing the amount and activity of CTSL. Forced enhancement of methylated histones protected histones from clipping during OIS, even under normoxia, but failed to block SAHFs. Altogether, these results suggest that maintenance of methylated histones is sufficient to protect histones from CTSL, not sufficient but necessary for inhibiting SAHFs, suggesting that besides inhibiting KDMs, hypoxia adopts other mechanisms to inhibit SAHFs. Hypoxia protects histones and chromatin from dramatic epigenetic changes by increasing methylated histones. Citation Format: Hyunsung Park, Soojeong Chang. Hypoxia increases the methylated histones to prevent histone clipping during Raf-induced senescence. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4766.